As CRISPR emerges, re­searchers spot­light pos­i­tive ef­fects in pre­na­tal gene edit­ing treat­ment for mice

In a break­through for the buzzing world of CRISPR re­search, a team of sci­en­tists has demon­strat­ed a use of the gene edit­ing tool to treat a ge­net­ic dis­ease in mice be­fore they are born.

The proof-of-con­cept study brings them one step clos­er — though still miles away — to the ul­ti­mate goal of treat­ing se­vere hu­man dis­eases di­ag­nosed ear­ly in preg­nan­cy, ac­cord­ing to the re­searchers from Chil­dren’s Hos­pi­tal of Philadel­phia and the Perel­man School of Med­i­cine at the Uni­ver­si­ty of Penn­syl­va­nia.

William Per­an­teau

“A sig­nif­i­cant amount of work needs to be done be­fore pre­na­tal gene edit­ing can be trans­lat­ed to the clin­ic,” said study co-leader William Per­an­teau, a pe­di­atric and fe­tal sur­geon in CHOP’s Cen­ter for Fe­tal Di­ag­no­sis and Treat­ment. “Nonethe­less, we are ex­cit­ed about the po­ten­tial of this ap­proach to treat ge­net­ic dis­eases of the liv­er and oth­er or­gans for which few ther­a­peu­tic op­tions ex­ist.”

For their study, pub­lished in Na­ture Med­i­cine, the team com­bined two dif­fer­ent tech­niques: Us­ing the well-known CRISPR-Cas9 com­pound as a guide, they fused an en­zyme to it that chem­i­cal­ly mod­i­fies the ge­net­ic code once the com­pound ar­rived at the spec­i­fied ge­net­ic lo­ca­tion. Dubbed base ed­i­tor 3, this method is de­scribed as po­ten­tial­ly safer than the cut-and-paste mod­el of reg­u­lar CRISPR-Cas9, which re­searchers have warned could cause off-tar­get ef­fects.

But be­fore they test­ed the tool on a group of mice en­gi­neered to de­vel­op the lethal liv­er dis­ease hered­i­tary ty­rosine­mia type 1 (HT1), the in­ves­ti­ga­tors first tried it out with the PC­SK9 gene — a cho­les­terol reg­u­la­tor now tar­get­ed by a new class of car­dio drugs — and showed that the fe­tus­es re­ceiv­ing this treat­ment were born with sig­nif­i­cant­ly low­er cho­les­terol lev­els.

Sim­i­lar­ly, the in­tend­ed ef­fect was ob­served in new­born mice which had a re­lat­ed gene — not the dis­ease-caus­ing one — dis­abled in utero: They “car­ried sta­ble amounts of edit­ed liv­er cells for up to three months af­ter the pre­na­tal treat­ment, with no ev­i­dence of un­want­ed, off-tar­get edit­ing at oth­er DNA sites” with “im­proved liv­er func­tion and pre­served sur­vival.”

In fact, they did even bet­ter than mice born with HT1 that are sub­se­quent­ly treat­ment with ni­tisi­none and di­et, the cur­rent stan­dard of care for in­fants with HT1.

The in­ves­ti­ga­tors re­main cau­tious­ly op­ti­mistic about their ear­ly work, al­ready test­ing al­ter­na­tive de­liv­ery sys­tems to the ade­n­ovirus vec­tors used in this ex­per­i­ment, as it’s been sug­gest­ed that ade­n­ovirus vec­tors, a main­stay in gene ther­a­py ex­per­i­ments, may cause ad­verse re­spons­es from the host’s im­mune sys­tem. Oth­er di­rec­tions of re­search in­clude di­rect­ly edit­ing dis­ease-caus­ing genes and ex­plor­ing the tech’s ap­pli­ca­tion in oth­er or­gans.

GSK's Hal Bar­ron her­alds their sec­ond pos­i­tive PhI­II for cru­cial an­ti-BC­MA ther­a­py, point­ing to a push for quick OKs in a crowd­ed field

Hal Barron has his second positive round of Phase III data in hand for his anti-BCMA antibody drug conjugate belantamab mafodotin (GSK2857916). And GSK’s research chief says the data paves the way for their drive in search of an FDA approval for treating multiple myeloma. 

It’s hard to overestimate the importance of this drug for GSK, a cornerstone of Barron’s campaign to make a dramatic impact on the oncology market and provide some long-lost excitement for the pharma giant’s pipeline. They’re putting this BCMA program at the front of that charge — looking to lead a host of rivals all aimed at the same target.

Martin Shkreli [via Getty]

Pris­on­er #87850-053 does not get to add drug de­vel­op­er to his list of cred­its

Just days after Retrophin shed its last ties to founder Martin Shkreli, the biotech is reporting that the lead drug he co-invented flopped in a pivotal trial. Fosmetpantotenate flunked both the primary and key secondary endpoints in a placebo-controlled trial for a rare disease called pantothenate kinase-associated neurodegeneration, or PKAN.

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UP­DAT­ED: An em­bold­ened As­traZeneca splurges $95M on a pri­or­i­ty re­view vouch­er. Where do they need the FDA to hus­tle up?

AstraZeneca is in a hurry.

We learned this morning that the pharma giant — not known as a big spender, until recently — forked over $95 million to get its hands on a priority review voucher from Sobi, otherwise known as Swedish Orphan Biovitrum.

That marks another step down on price for a PRV, which allows the holder to slash 4 months off of any FDA review time.

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We­bi­nar: Re­al World End­points — the brave new world com­ing in build­ing fran­chise ther­a­pies

Several biopharma companies have been working on expanding drug labels through the use of real world endpoints, combing through the data to find evidence of a drug’s efficacy for particular indications. But we’ve just begun. Real World Evidence is becoming an important part of every clinical development plan, in the soup-through-nuts approach used in building franchises.

I’ve recruited a panel of 3 top experts in the field — the first in a series of premium webinars — to look at the practical realities governing what can be done today, and where this is headed over the next few years, at the prodding of the FDA.

ZHEN SU — Merck Serono’s Senior Vice President and Global Head of Oncology
ELLIOTT LEVY — Amgen’s Senior Vice President of Global Development
CHRIS BOSHOFF — Pfizer Oncology’s Chief Development Officer

A premium subscription to Endpoints News is required to attend this webinar. Please upgrade to either an Insider or Enterprise plan for access. Already have Endpoints Premium? Please sign-in below. You can contact our Subscriptions team at with any issues.

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Brian Kaspar. AveXis via Twitter

AveX­is sci­en­tif­ic founder fires back at No­var­tis CEO Vas Narasimhan, 'cat­e­gor­i­cal­ly de­nies any wrong­do­ing'

Brian Kaspar’s head was among the first to roll at Novartis after company execs became aware of the fact that manipulated data had been included in its application for Zolgensma, now the world’s most expensive therapy.

But in his first public response, the scientific founder at AveXis — acquired by Novartis for $8.7 billion — is firing back. And he says that not only was he not involved in any wrongdoing, he’s ready to defend his name as needed.

I reached out to Brian Kaspar after Novartis put out word that he and his brother Allen had been axed in mid-May, two months after the company became aware of the allegations related to manipulated data. His response came back through his attorneys.

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Bob Smith, Pfizer

Pfiz­er is mak­ing a $500M state­ment to­day: Here’s how you be­come a lead play­er in the boom­ing gene ther­a­py sec­tor

Three years ago, Pfizer anted up $150 million in cash to buy Bamboo Therapeutics in Chapel Hill, NC as it cautiously stuck a toe in the small gene therapy pool of research and development.

Company execs followed up a year later with a $100 million expansion of the manufacturing operations they picked up in that deal for the UNC spinout, which came with $495 million in milestones.

And now they’re really going for it.

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Video: Putting the AI in R&D — with Badhri Srini­vasan, Tony Wood, Rosana Kapeller, Hugo Ceule­mans, Saurabh Sa­ha and Shoibal Dat­ta

During BIO this year, I had a chance to moderate a panel among some of the top tech experts in biopharma on their real-world use of artificial intelligence in R&D. There’s been a lot said about the potential of AI, but I wanted to explore more about what some of the larger players are actually doing with this technology today, and how they see it advancing in the future. It was a fascinating exchange, which you can see here. The transcript has been edited for brevity and clarity. — John Carroll

UP­DAT­ED: As­traZeneca’s Imfinzi/treme com­bo strikes out — again — in lung can­cer. Is it time for last rites?

AstraZeneca bet big on the future of their PD-L1 Imfinzi combined with the experimental CTLA-4 drug tremelimumab. But once again it’s gone down to defeat in a major Phase III study — while adding damage to the theory involving targeting cancer with a high tumor mutational burden.

Early Wednesday the pharma giant announced that their NEPTUNE study had failed, with the combination unable to beat standard chemo at overall survival in high TMB cases of advanced non-small cell lung cancer. We won’t get hard data until later in the year, but the drumbeat of failures will call into question what — if any — future this combination can have left.

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Am­gen, Al­ler­gan biosim­i­lar of Roche's block­buster Rit­ux­an clears an­oth­er US piv­otal study 

Novartis $NVS may have given up, but Amgen $AMGN and Allergan $AGN are plowing ahead with their knockoff of Roche’s blockbuster biologic Rituxan in the United States.

Their copycat, ABP 798, was found to have a clinically equivalent impact as Rituxan — meeting the main goal of the study involving CD20-positive B-cell non-Hodgkin’s lymphoma patients. This is the second trial supporting the profile of the biosimilar. In January, it came through with positive PK results in patients with rheumatoid arthritis.